# Hyperglycemia-Induced Endothelial Dysfunction: From Classical Pathogenetic Mechanisms to Emerging Insights into ACE2 Protective Action

## TL;DR

This paper reviews how high blood sugar causes blood vessel damage in diabetes and explores new ways to protect blood vessels, like the ACE2 protein.

## Contribution

The paper highlights the emerging role of ACE2 as a protective factor against hyperglycemia-induced endothelial dysfunction.

## Key findings

- Hyperglycemia causes endothelial dysfunction through mechanisms like oxidative stress and inflammation.
- ACE2 shows potential as a therapeutic target due to its vasoprotective and anti-inflammatory effects.
- Understanding these mechanisms is key to developing strategies to prevent diabetic vascular complications.

## Abstract

Diabetes is a pivotal risk factor for cardiovascular disease as well as microvascular complications, including retinopathy and nephropathy. Chronic hyperglycemia is a key player in linking diabetes with endothelial dysfunction which, in turn, contributes to cardiovascular disease. Indeed, hyperglycemia acts as a trigger for endothelial dysfunction, promoting a shift in the endothelium from a protective, anti-inflammatory state to a dysfunctional, injury-prone phenotype. A hyperglycemic environment triggers several pathogenetic mechanisms, including alterations in bioenergetics, production of advanced glycation end products, oxidative stress and mitochondrial dysfunction, all contributing to endothelial dysfunction. The activation of these pathophysiological mechanisms by hyperglycemia culminates in reduced nitric oxide production, as well as the induction of oxidative stress and inflammation, all of which are pivotal in impairing endothelial homeostasis and promoting cellular damage. Besides these classical mechanisms, there is growing attention on novel pathogenetic factors linking diabetic hyperglycemia with endothelial dysfunction, such as the ACE2 protein. The latter is emergeing for its potential to counter hyperglycemia-induced cellular damage through its vasoprotective and anti-inflammatory actions, making it a promising therapeutic target for tackling endothelial dysfunction. This review provides an overview of classical as well as emerging mechanisms underpinning the deleterious effects of diabetic hyperglycemia on endothelial dysfunction. In turn, understanding the molecular interconnections between hyperglycemia and endothelial dysfunction is crucial for developing novel strategies to restore endothelial homeostasis and mitigate diabetic vascular complications.